According to the World Health Organization (WHO), in 2009, more than 220 million people worldwide have diabetes. In 2005, an estimated at least 1.1 million people died from diabetes. The WHO projects that diabetes deaths will double between 2005 and 2030.
Diabetes is a chronic disease that occurs either when the beta-cells in pancreas do not produce enough insulin or when the body cannot effectively use the insulin it produces. Insulin is a hormone that regulates blood sugar. Hyperglycaemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially the nerves and blood vessels. Type II diabetes (formerly called non-insulin-dependent or adult-onset) results from the body's ineffective use of insulin. Type II diabetes comprises 90% of people with diabetes around the world, and is often the result of excess body weight and physical inactivity. Effective control of blood glucose levels in diabetes patients will prevent or delay the development of diabetes complications such as cardiovascular diseases, stroke, nephropathy, retinopathy, renal failure, amputation of the extremities, and beta cell failure.
Glucose molecules pass from the bloodstream into glomerulus in the kidney, but the glucose is subsequently reabsorbed via active transport mechanisms in the proximal convoluted tubule back to the blood circulation rather than being lost with the urine. Two sodium-dependent glucose co-transporters have been identified that cause the glucose to be reabsorbed: SGLT-1 and SGLT-2. SGLT-2, which is found only in the earlier section (S1 segment) of the proximal convoluted tubule of the glomerulus, accounts for approximately 90% of the reabsorption of glucose. The other, SGLT-1, which exists in the later section (S3 segment) of the proximal tubule and is also found in the gut and other tissues, accounts for only about 10% of glucose reabsorption. In people with normal blood glucose levels, glucose is not excreted into the urine, due to the function of SGLTs.
Selective inhibitors of SGLT-2 have been demonstrated in both preclinical animal models and human clinical trials to effectively control glucose levels in the blood as well as lowering HbA1C (Han et al., Diabetes, 57(6):1723 (2008); List et al., Diabetes Care, 32(4):650 (2009); Komoroski et al., Clin. Pharmacol. Ther., 85(5):520 (2009); Komoroski et al., Clin. Pharmacol. Ther., 85(5):513 (2009)). In these studies, body weight reduction was often observed, indicating that SGLT-2 inhibitors could lower body weight. Humans with a mutation of the SGLT-2 gene have familial forms of renal glucosuria, providing further evidence of the primary role of SGLT-2 in renal glucose re-absorption. These patients have otherwise normal renal functions and generally have no other clinical abnormalities.
In recent years, reducing HbA1C values to <7% has become the recommended standard for patients with type II diabetes. Although there are a variety of medical therapies for type II diabetes, many patients still cannot achieve the target HbA1C level. Since all of these oral agents, except for α-glucosidase inhibitors, directly or indirectly depend on insulin to regulate blood glucose levels, type II diabetes patients eventually will rely on insulin therapy because of an inevitable decline of beta-cell function. In addition, the existing agents do not promote weight loss and some even cause weight gain. Clearly, there is an imperative demand for novel agents for the effective treatment of type II diabetes which are independent of insulin.
The present invention is directed to overcoming these and other deficiencies in the art.